Vasoactive intestinal peptide (VIP) and its type I and II G protein-coupled receptors, VPAC1R and VPAC2R, are prominent in the mammalian immune system and regulate many aspects of innate and adaptive immunity. VPAC1R is expressed constitutively by T cells, whereas VPAC2R on T cells is induced and repressed by numerous immune factors. Constitutive expression of VPAC2R selectively in CD4+ T cells of transgenic (TG) C57BL/6 mice evokes production of more Th2-type IL-4 and IL-5, and less Th1-type IFNgamma after T cell receptor (TCR) activation with consequent in vivo elevation of blood IgE, IgG1 and eosinophils. CD4+ T cell-VPAC2 R TG mice show enhanced IgE antibody responses and cutaneous immediate-type hypersensitivity, and depressed delayed- type hypersensitivity (DTH). In contrast, VPAC2 Rnull (K/O) C57BL/6 mice exhibit significantly heightened hapten-evoked cutaneous DTH, suppressed generation of IgE anti-hapten antibodies and depressed active cutaneous anaphylaxis, as a result of production of more Th1-type IFN-gamma and less Th2-type IL-4 and IL-5 after TCR activation. The higher than normal Th2/Th1 ratio for VPAC2R-TG mice and higher than normal Th1/Th2 ratio for VPAC2R-null mice will be elucidated by studies to: 1) assess diverse ex vivo functional responses to VIP of CD4+ and CD8+ T cells from VPAC2R-null mice with only VPAC1Rs and from VPAC2R-TG mice with a vast predominance of VPAC2Rs; 2) delineate roles of endogenous VIP-VPACR systems in development and activation of T cells in VPAC2R-null and VPAC2R-TG mice using existing anti-VIP peptidolytic antibodies to eliminate VIP and newly-developed antagonistic anti-VPAC1R and anti-VPAC2R rat MoAbs to block each VPACR at different stages of maturation; 3) analyze critical transcriptional and signaling pathways by which the VIP-VPAC2R system differentially regulates lineage commitment of Th1 and Th2 cells; and 4) investigate effects of VIP-VPAC2R-mediated skewing of Th1/Th2 balance on host defense and immunopathogenic reactions in VPAC2R-null and VPAC2R-TG mice. VPAC2R agonist drugs thus are expected to augment mobilization of CD4+ T cells in normal immune responses, whereas VPAC2R antagonists may contribute to termination of hypersensitivity reactions and correction of T cell immune deficiencies.